The process of drug discovery is presently undergoing a fundamental revolution as the era of functional genomics comes of age. The term “functional genomics” applies to an approach utilising bioinformatics tools to ascribe function to protein sequences of interest. Such tools are becoming increasingly necessary as the speed of generation of sequence data is rapidly outpacing the ability of research laboratories to assign functions to these protein sequences.
As bioinformatics tools increase in potency and in accuracy, these tools are rapidly replacing the conventional techniques of biochemical characterisation. Indeed, the advanced bioinformatics tools used in identifying the present invention are now capable of outputting results in which a high degree of confidence can be placed.
Various institutions and commercial organisations are examining sequence data as they become available and significant discoveries are being made on an on-going basis. However, there remains a continuing need to identify and characterise further genes and the polypeptides that they encode, as targets for research and for drug discovery.
Introduction
Secreted Proteins
The ability for cells to make and secrete extracellular proteins is central to many biological processes. Enzymes, growth factors, extracellular matrix proteins and signalling molecules are all secreted by cells. This is through fusion of a secretory vesicle with the plasma membrane. In most cases, but not all, proteins are directed to the endoplasmic reticulum and into secretory vesicles by a signal peptide. Signal peptides are cis-acting sequences that affect the transport of polypeptide chains from the cytoplasm to a membrane bound compartment such as a secretory vesicle. Polypeptides that are targeted to the secretory vesicles are either secreted into the extracellular matrix or are retained in the plasma membrane. The polypeptides that are retained in the plasma membrane will have one or more transmembrane domains. Examples of secreted proteins that play a central role in the functioning of a cell are cytokines, hormones, extracellular matrix proteins (adhesion molecules), proteases, and growth and differentiation factors. Description of some of the properties of these proteins follows.
Defensins
Defensins form part of the body's innate immune system that acts against invasion by foreign pathogens. Mammalian defensins are split into three categories; alpha, beta and theta, based upon the pattern of disulphide bonds. INSP108 and INSP109 fall into the beta category. These proteins are cationic and arginine-rich and share a typical tertiary structure despite differences in primary structure. They consist of three antiparallel beta sheets connected by loops, and a beta hairpin with hydrophobic properties protrudes orthagonally.
These proteins have been shown to have a broad spectrum of activity ranging from Gram-positive and Gram-negative bacteria to mycobacteria, fungi and even enveloped viruses. They bind to the phospholipid-rich negatively charged cell membranes of microbes and cause disruption, though the exact mode of action is yet to be determined. High concentrations are cytotoxic for mammalian cells, though it has been shown that lower concentrations promote growth in epithelial cells and fibroblasts, thus suggesting a role in wound healing. Defensins have also been shown to be chemotactic for monocytes, polymorphonuclear leucocytes and T-cells. In vitro defensins have been shown to be active against E. coli, Listeria monocytogenes, Salmonella typhimurium and Candida albicans. 
Increasing knowledge of these proteins is therefore of extreme importance in increasing the understanding of the underlying pathways that lead to the disease states and associated disease states mentioned above, and in developing more effective gene and/or drug therapies to treat these disorders.